Identifying differential interactions of traumatic experiences with genetic risk for posttraumatic stress disorder

Identifying differential interactions of traumatic experiences with genetic risk for posttraumatic stress disorder | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Identifying differential interactions of traumatic experiences with genetic risk for posttraumatic stress disorder Jacob Knyspel, Saakshi Kakar, Anna Carnegie, Gursharan Kalsi, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8320002/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Background: Posttraumatic stress disorder (PTSD) occurs following traumatic experiences, but not everyone who experiences trauma develops PTSD. Genetic factors play an important role in shaping how individuals respond to trauma, a form of gene-environment interaction. An open question in PTSD genetics research is the extent to which gene-environment interactions vary across specific traumas. Objective: We aimed to compare gene-environment interaction effects across a broad range of self-reported traumatic experiences across the lifespan. Method: We analysed existing data from two large UK cohorts: the UK Biobank and GLAD-EDGI-COPING (N=144,702). PTSD symptoms were assessed using the six-item abbreviated PTSD Checklist. We examined eleven self-reported trauma exposures, including five childhood traumas and six adulthood traumas. We conducted gene-environment interaction analyses for each trauma at three levels of genetic specificity: polygenic risk scores, specific genes, and specific genetic variants. Results: Childhood traumas had stronger associations with PTSD symptoms and greater gene-environment interactions than adulthood traumas on average. Childhood emotional and physical neglect also had gene-environment greater interactions than childhood abuse. Interaction patterns varied across genes and variants, with several leading PTSD-associated genes (e.g. ANAPC, FAM120A, SGCD ) having particularly great interactions with certain traumas. Several genes ( DTX4, PSMD12, TYW3, ZNF660 ) demonstrated consistently stronger interactions with all childhood or all adulthood traumas. Differences in gene-environment interactions across traumas were not explained by variation in exposure rates, associations with PTSD, or gene-environment correlations. Conclusions: Genetic influences on PTSD risk vary by trauma type and are most pronounced for childhood traumas. To account for the moderating role of trauma type, genetic research on PTSD should incorporate detailed trauma exposure information. Biological sciences/Genetics Health sciences/Diseases/Psychiatric disorders/Post-traumatic stress disorder PTSD trauma genetics polygenic risk scores gene-environment interaction Full Text Additional Declarations The authors declare no competing interests. Supplementary Files ptsdgxesupplementarymethod20260211.docx Supplementary Methods ptsdgxesupplementarytables20260211.xlsx Supplementary Tables Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8320002","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":571245614,"identity":"e0f0d1f1-fec3-46f3-8bb8-51ad2b15b429","order_by":0,"name":"Jacob Knyspel","email":"","orcid":"https://orcid.org/0000-0001-5600-4826","institution":"Institute of Psychiatry, Psychology \u0026 Neuroscience, King's College London","correspondingAuthor":false,"prefix":"","firstName":"Jacob","middleName":"","lastName":"Knyspel","suffix":""},{"id":571245615,"identity":"9f685a13-55d6-4e4d-8e68-0cb4f9fc863e","order_by":1,"name":"Saakshi 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disorder","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"PTSD, trauma, genetics, polygenic risk scores, gene-environment interaction","lastPublishedDoi":"10.21203/rs.3.rs-8320002/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8320002/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Posttraumatic stress disorder (PTSD) occurs following traumatic experiences, but not everyone who experiences trauma develops PTSD. Genetic factors play an important role in shaping how individuals respond to trauma, a form of gene-environment interaction. An open question in PTSD genetics research is the extent to which gene-environment interactions vary across specific traumas.\u003c/p\u003e\n\u003cp\u003eObjective: We aimed to compare gene-environment interaction effects across a broad range of self-reported traumatic experiences across the lifespan.\u003c/p\u003e\n\u003cp\u003eMethod: We analysed existing data from two large UK cohorts: the UK Biobank and GLAD-EDGI-COPING (N=144,702). PTSD symptoms were assessed using the six-item abbreviated PTSD Checklist. We examined eleven self-reported trauma exposures, including five childhood traumas and six adulthood traumas. We conducted gene-environment interaction analyses for each trauma at three levels of genetic specificity: polygenic risk scores, specific genes, and specific genetic variants.\u003c/p\u003e\n\u003cp\u003eResults: Childhood traumas had stronger associations with PTSD symptoms and greater gene-environment interactions than adulthood traumas on average. Childhood emotional and physical neglect also had gene-environment greater interactions than childhood abuse. Interaction patterns varied across genes and variants, with several leading PTSD-associated genes (e.g. \u003cem\u003eANAPC, FAM120A, SGCD\u003c/em\u003e) having particularly great interactions with certain traumas. Several genes\u003cem\u003e \u003c/em\u003e(\u003cem\u003eDTX4, PSMD12, TYW3, ZNF660\u003c/em\u003e) demonstrated consistently stronger interactions with all childhood or all adulthood traumas. Differences in gene-environment interactions across traumas were not explained by variation in exposure rates, associations with PTSD, or gene-environment correlations.\u003c/p\u003e\n\u003cp\u003eConclusions: Genetic influences on PTSD risk vary by trauma type and are most pronounced for childhood traumas. To account for the moderating role of trauma type, genetic research on PTSD should incorporate detailed trauma exposure information.\u003c/p\u003e","manuscriptTitle":"Identifying differential interactions of traumatic experiences with genetic risk for posttraumatic stress disorder","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2026-03-18 17:54:58","doi":"10.21203/rs.3.rs-8320002/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2026-01-08 06:21:44","doi":"10.21203/rs.3.rs-8320002/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6549d8b0-ae13-48ca-801f-11556ad38fdb","owner":[],"postedDate":"March 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":60789149,"name":"Biological sciences/Genetics"},{"id":60789150,"name":"Health sciences/Diseases/Psychiatric disorders/Post-traumatic stress disorder"}],"tags":[],"updatedAt":"2026-01-08T13:48:37+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-18 17:54:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-8320002","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8320002","identity":"rs-8320002","version":["v2"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}